Introduction

Plasminogen, human-tmvh is a plasma-derived human plasminogen blood derivative.

Uses for Plasminogen, Human-tmvh

Plasminogen, human-tmvh has the following uses:

Plasminogen, human-tmvh is indicated for the treatment of patients with plasminogen deficiency type 1 (hypoplasminogenemia). Plasminogen, human-tmvh has been designated an orphan drug by FDA for use in the treatment of this condition.

Efficacy of plasminogen, human-tmvh has been evaluated in an open-label clinical trial in 15 patients (9 adults and 6 pediatric patients 4–16 years of age) with plasminogen deficiency type 1. All patients received plasminogen, human-tmvh 6.6 mg/kg IV every 2–4 days for 48 weeks to achieve an increase in trough plasminogen activity of at least 10% above baseline and to treat clinical manifestations of the disease. All patients with any lesions at baseline achieved at least 50% improvement in the number/size of their lesions. At the end of the 48-week study, 25 of 32 external lesions (78%) and 9 of 12 assessed internal lesions (75%) were resolved; no recurrent or new lesions were observed or identified on imaging studies through week 48.

Plasminogen, Human-tmvh Dosage and Administration

General

Plasminogen, human-tmvh is available in a single-dose 50-mL vial containing 68.8 mg of plasminogen as a lyophilized powder for reconstitution with 12.5 mL of sterile water for injection. After reconstitution, each vial will contain 5.5 mg/mL of plasminogen.

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

For IV use after reconstitution only.

Plasminogen, human-tmvh lyophilized powder should be reconstituted as directed by the manufacturer to provide a 5.5-mg/mL solution. The solution should be prepared within 3 hours of administration. The prepared dose of plasminogen, human-tmvh should be administered slowly over 10–30 minutes (i.e., approximately 1 mL every 12 seconds) into a peripheral vein using an appropriately sized administration syringe connected through a syringe disc filter to a butterfly infusion set.

Pediatric Patients

Dosage and Administration

The recommended dosage of plasminogen, human-tmvh for the treatment of plasminogen deficiency type 1 in pediatric patients is 6.6 mg/kg administered IV every 2–4 days. The frequency of administration is based on plasminogen activity level and clinical status of lesions. The manufacturer's labeling should be consulted for detailed information on interpretation of plasminogen activity level and determination of dosing frequency.

Adults

Dosage and Administration

The recommended dosage of plasminogen, human-tmvh for the treatment of plasminogen deficiency type 1 in adults is 6.6 mg/kg administered IV every 2–4 days. The frequency of administration is based on plasminogen activity level and clinical status of lesions. The manufacturer's labeling should be consulted for detailed information on interpretation of plasminogen activity level and determination of dosing frequency.

Contraindications

Plasminogen, human-tmvh is contraindicated in patients with known hypersensitivity to plasminogen or to other components of plasminogen, human-tmvh.

Warnings/Precautions

Bleeding

Patients with plasminogen deficiency type 1 may bleed from active mucosal disease-related lesions during plasminogen, human-tmvh therapy. Depending on the lesion sites, this may manifest as gastrointestinal (GI) bleeding, hemoptysis, epistaxis, vaginal bleeding, or hematuria.

Plasminogen, human-tmvh may worsen active bleeding not related to disease lesions. One patient with a recent history of GI bleeding due to gastric ulcers experienced GI bleeding two days after receiving the second dose of plasminogen, human-tmvh. The patient received plasminogen, human-tmvh through a compassionate use program and the dose was 6.6 mg/kg every 2 days. Endoscopy showed multiple ulcers with one actively bleeding ulcer near the pylorus. Given the mechanism of action of plasminogen in fibrinolysis, it is possible that plasminogen, human-tmvh played a role in either prolonging or worsening the active bleeding. Plasminogen, human-tmvh has not been studied in patients at increased risk for bleeding due to disease or injury.

Prior to initiation of treatment with plasminogen, human-tmvh, confirm healing of lesions or wounds suspected as a source of a recent bleeding event. Plasminogen, human-tmvh may prolong or worsen bleeding in patients with bleeding diatheses or in patients taking anticoagulants and/or antiplatelet drugs and other agents that may interfere with normal coagulation. Monitor patients during and for 4 hours after infusion when administering plasminogen, human-tmvh to patients with bleeding diatheses and patients taking anticoagulants, antiplatelet drugs, or other agents that may interfere with normal coagulation. If a patient develops uncontrolled bleeding (defined as any GI bleeding or bleeding from any other site that persists longer than 30 minutes), seek emergency care and discontinue plasminogen, human-tmvh immediately.

Tissue Sloughing

Tissue sloughing at mucosal sites may occur after initiation of treatment with plasminogen, human-tmvh as plasminogen activity levels are restored to physiologic levels and fibrinolysis occurs. Lesions in the respiratory, GI, and genitourinary systems may slough following treatment resulting in bleeding or organ obstruction. Patients with tracheobronchial lesions may develop airway obstruction or hemoptysis. Closely monitor patients with either confirmed or suspected airway disease as manifested by cough, wheezing, shortness of breath, or changes in speech (dysphonia). Initiate the treatment with plasminogen, human-tmvh in an appropriate clinical setting with personnel trained in airway management and readily available respiratory support equipment. Monitor at-risk patients in such a setting for a minimum of 4 hours after their first dose of plasminogen, human-tmvh.

Patients with GI and genitourinary lesions may experience tissue sloughing that causes pain, bleeding, or passage of tissue from affected organ systems. Patients should report persistent abdominal, flank, or pelvic pain to their clinician.

Transmission of Infectious Agents

Because plasminogen, human-tmvh is derived from human plasma, it carries a risk of transmitting infectious agents. Based on effective donor screening and product manufacturing processes, plasminogen, human-tmvh carries a remote risk for transmission of viral diseases and variant Creutzfeldt-Jakob disease (vCJD). There is a theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD), but, if that risk actually exists, the risk of transmission would also be considered extremely low. It is also possible that unknown infectious agents may be present in plasminogen, human-tmvh. The risk of infectious agent transmission has been reduced by screening plasma donors for prior exposure to certain viruses, testing for the presence of certain current virus infections, and including virus inactivation/removal steps in the manufacturing process for plasminogen, human-tmvh.

Report any infection thought to be possibly transmitted by plasminogen, human-tmvh to Prometic at 800-735-4086 and [email protected], or FDA at 800-FDA-1088 or [Web].

Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylaxis, may occur with plasminogen, human-tmvh. In case of a hypersensitivity reaction, discontinue plasminogen, human-tmvh immediately and treat according to standard medical practice.

Neutralizing Antibodies

Formation of neutralizing antibodies (inhibitors) to plasminogen following the administration of plasminogen, human-tmvh has not been reported to date. Monitor patients for the loss of clinical efficacy as manifested by the development of new or recurrent lesions while on plasminogen, human-tmvh therapy, and obtain plasminogen activity trough levels to confirm that adequate plasminogen activity levels have been achieved and are being maintained.

Laboratory Abnormalities

Patients receiving plasminogen, human-tmvh may have elevated levels of D-dimer in blood. Intepret D-dimer levels with caution in patients being screened for venous thromboembolism (VTE), as elevated levels may be associated with the physiologic activity of plasminogen, human-tmvh (fibrinolysis of ligneous lesions) and not indicative of VTE. Consider other tests to screen for VTE in patients receiving plasminogen, human-tmvh, as D-dimer levels will lack interpretability.

Specific Populations

Pregnancy

Risk Summary: There are no clinical trials of plasminogen, human-tmvh use in pregnant women. No animal reproductive and developmental toxicity studies have been conducted with plasminogen, human-tmvh to assess whether it can cause fetal harm when administered to a pregnant woman. In the United States, the background risk of major birth defects is about 3%, and miscarriage occurs in up to 20% of clinically recognized pregnancies.

Lactation

Endogenous plasminogen is distributed into human milk; however, there is no information available on the presence of plasminogen, human-tmvh in human milk, the effects on the breast-fed infant, or the effects on milk production. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for plasminogen, human-tmvh and any potential adverse effects on the breast-fed infant from plasminogen, human-tmvh or from the underlying maternal condition.

Pediatric Use

The safety and efficacy of plasminogen, human-tmvh have been established in pediatric patients. Use of plasminogen, human-tmvh is supported by the two clinical trials and by expanded access and compassionate use programs that included 18 pediatric patients 11 months to 17 years of age.

Geriatric Use

The safety and efficacy of plasminogen, human-tmvh have not been established in geriatric patients. Clinical studies of plasminogen, human-tmvh for this indication did not include patients 65 years of age and older. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Common Adverse Effects

The most frequent (incidence ≥10%) adverse reactions in clinical trials were abdominal pain, bloating, nausea, fatigue, extremity pain, hemorrhage, constipation, dry mouth, headache, dizziness, arthralgia, and back pain.

General

Plasminogen, human-tmvh is available in a single-dose 50-mL vial containing 68.8 mg of plasminogen as a lyophilized powder for reconstitution with 12.5 mL of sterile water for injection. After reconstitution, each vial will contain 5.5 mg/mL of plasminogen.

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

For IV use after reconstitution only.

Plasminogen, human-tmvh lyophilized powder should be reconstituted as directed by the manufacturer to provide a 5.5-mg/mL solution. The solution should be prepared within 3 hours of administration. The prepared dose of plasminogen, human-tmvh should be administered slowly over 10–30 minutes (i.e., approximately 1 mL every 12 seconds) into a peripheral vein using an appropriately sized administration syringe connected through a syringe disc filter to a butterfly infusion set.

Pediatric Patients

Dosage and Administration

The recommended dosage of plasminogen, human-tmvh for the treatment of plasminogen deficiency type 1 in pediatric patients is 6.6 mg/kg administered IV every 2–4 days. The frequency of administration is based on plasminogen activity level and clinical status of lesions. The manufacturer's labeling should be consulted for detailed information on interpretation of plasminogen activity level and determination of dosing frequency.

Adults

Dosage and Administration

The recommended dosage of plasminogen, human-tmvh for the treatment of plasminogen deficiency type 1 in adults is 6.6 mg/kg administered IV every 2–4 days. The frequency of administration is based on plasminogen activity level and clinical status of lesions. The manufacturer's labeling should be consulted for detailed information on interpretation of plasminogen activity level and determination of dosing frequency.

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Please see product labeling for drug interaction information.